The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders
Open accessAbstract
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.
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Molecular and pathological evidence implicates later pregnancy and early postnatal life, pointing to altered neuronal connectivity and signaling pathways under intense development in these periods.
“Later pregnancy and early postnatal life are additionally implicated by accumulating molecular and pathological evidence pointing to altered neuronal connectivity and a resultant perturbation in signaling pathways, systems under intense development in these periods.25,26”
From Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence (2014) · cites this paper as [26]
Evidence supporting environmental contributions to ASD risk includes incomplete concordance for autism among monozygotic twins and incomplete penetrance within individuals expressing a given ASD-linked gene mutation.
“Evidence supporting environmental contributions to ASD risk include observations of incomplete concordance for autism among monozygotic twins and incomplete penetrance within individuals expressing a given ASD-linked gene mutation, whereby a significant percentage of carriers do not express autistic phenotypes [ 14 , 19 , 22 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [19]
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RetractedGABRB2, a key player in neuropsychiatric disorders and beyond.
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The autism risk genes MET and PLAUR differentially impact cortical development
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- Authors
- Levitt, P., & Campbell, D. B.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Levitt, Pat
- ORCID
- Levitt, Pat
- Venue
- Journal of Clinical Investigation
- Published
- 2009-04-01
- Volume
- 119
- Issue
- 4
- Pages
- 747-754
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2662567
- OpenAlex
- W2018736722
- Cited by
- 234
- References
- 115
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 18 · 2016: 13 · 2015: 14 · 2014: 27 · 2013: 16 · 2012: 26
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- autism spectrum disorder, genetic etiology, de novo mutations, common genetic variants, ERK signaling, PI3K signaling, receptor tyrosine kinase, neurodevelopmental syndrome, neurodevelopmental disorders
- MeSH terms
- Alleles, Autistic Disorder, Child, Female, Humans, Male, Models, Genetic, Models, Neurological, Mutation, Proto-Oncogene Proteins, Genetic Variation, Signal Transduction, Receptors, Growth Factor, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Genetic Predisposition to Disease, MAP Kinase Signaling System, Genome-Wide Association Study
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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